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Molecular and Cellular Biology, October 2007, p. 6842-6851, Vol. 27, No. 19
0270-7306/07/$08.00+0     doi:10.1128/MCB.00815-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Sorting by the Cytoplasmic Domain of the Amyloid Precursor Protein Binding Receptor SorLA ^,

The MIND-center, Department of Medical Biochemistry,¹ Stereology and Electron Microscopy Research Laboratory, University of Aarhus, 8000 Aarhus, Denmark,² Department of Biology, Chemistry and Pharmacology, Free University of Berlin, Berlin, Germany,³ Department of Molecular Cell Biology, University of Oslo, Oslo, Norway,⁴ Department of Cell Biology, UMCU, Utrecht, The Netherlands,⁵ Department of Biochemistry and Molecular Cell Biology, University of Göttingen, Göttingen, Germany,⁶ Institute of Physiological Chemistry and Pathobiochemistry, University of Münster, Münster, Germany⁷

Received 9 May 2007/ Returned for modification 16 July 2007/ Accepted 16 July 2007

SorLA/LR11 (250 kDa) is the largest and most composite member of the Vps10p-domain receptors, a family of type 1 proteins preferentially expressed in neuronal tissue. SorLA binds several ligands, including neurotensin, platelet-derived growth factor-bb, and lipoprotein lipase, and via complex-formation with the amyloid precursor protein it downregulates generation of Alzheimer's disease-associated Aß-peptide. The receptor is mainly located in vesicles, suggesting a function in protein sorting and transport. Here we examined SorLA's trafficking using full-length and chimeric receptors and find that its cytoplasmic tail mediates efficient Golgi body-endosome transport, as well as AP-2 complex-dependent endocytosis. Functional sorting sites were mapped to an acidic cluster-dileucine-like motif and to a GGA binding site in the C terminus. Experiments in permanently or transiently AP-1 µ1-chain-deficient cells established that the AP-1 adaptor complex is essential to SorLA's transport between Golgi membranes and endosomes. Our results further implicate the GGA proteins in SorLA trafficking and provide evidence that SNX1 and Vps35, as parts of the retromer complex or possibly in a separate context, are engaged in retraction of the receptor from endosomes.

Published ahead of print on 23 July 2007.

Supplemental material for this article may be found at http://mcb.asm.org/.

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